Brain Extracellular Space: The Final Frontier of Neuroscience
Open accessAbstract
Brain extracellular space is the narrow microenvironment that surrounds every cell of the central nervous system. It contains a solution that closely resembles cerebrospinal fluid with the addition of extracellular matrix molecules. The space provides a reservoir for ions essential to the electrical activity of neurons and forms an intercellular chemical communication channel. Attempts to reveal the size and structure of the extracellular space using electron microscopy have had limited success; however, a biophysical approach based on diffusion of selected probe molecules has proved useful. A point-source paradigm, realized in the real-time iontophoresis method using tetramethylammonium, as well as earlier radiotracer methods, have shown that the extracellular space occupies ∼20% of brain tissue and small molecules have an effective diffusion coefficient that is two-fifths that in a free solution. Monte Carlo modeling indicates that geometrical constraints, including dead-space microdomains, contribute to the hindrance to diffusion. Imaging the spread of macromolecules shows them increasingly hindered as a function of size and suggests that the gaps between cells are predominantly ∼40 nm with wider local expansions that may represent dead-spaces. Diffusion measurements also characterize interactions of ions and proteins with the chondroitin and heparan sulfate components of the extracellular matrix; however, the many roles of the matrix are only starting to become apparent. The existence and magnitude of bulk flow and the so-called glymphatic system are topics of current interest and controversy. The extracellular space is an exciting area for research that will be propelled by emerging technologies.
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The relative abundance of CS isomers incorporated into CS-GAG chains has been linked to key biological functions within the brain, including charged molecule diffusion (0S-CS), neurocircuit plasticity (4S-CS and 6S-CS), glial scarring (4S6S-CS), and neurite outgrowth (2S6S-CS).
“The relative abundance of CS isomers incorporated into the CS-GAG chains has been linked to key biological functions within the brain including charged molecule diffusion (0S-CS (Nicholson & Hrabětová 2017)), neurocircuit plasticity (4S-CS and 6S-CS (Miyata et al. 2012; Yang et al. 2021)), glial scarring (4S6S-CS (Brown et al. 2012)), and neurite outgrowth (2S6S-CS (Shida et al. 2019; Clement et a”
From Perineuronal net deglycosylation associates with tauopathy‐induced gliosis and neurodegeneration (2024) · cites this paper as Nicholson & Hrabětová 2017
The citation to Nicholson and Hrabětová is attached to charged-molecule diffusion (0S-CS), not the other functions in the sentence. In “Extracellular matrix and the control of ECS properties” (page unavailable), the paper reports that chondroitin sulfate affects Ca2+ diffusion, but it does not identify the 0S-CS isomer or link its relative abundance to that effect. (LLM, conf=0.87)
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- Authors
- Nicholson, C., & Hrabětová, S.
- Affiliations
- SUNY Downstate Health Sciences University (US)
- State University of New York (US)
- Corresponding author
- Nicholson, Charles
- Venue
- Biophysical Journal
- Publisher
- Elsevier BV
- Published
- 2017-11
- Volume
- 113
- Issue
- 10
- Pages
- 2133-2142
- ISSN
- 0006-3495 (ISSN-L)
- PMC
- PMC5700249
- OpenAlex
- W2737379596
- Cited by
- 321
- References
- 62
- Citations by year
- 2026: 28 · 2025: 40 · 2024: 35 · 2023: 51 · 2022: 44 · 2021: 41 · 2020: 31 · 2019: 28 · 2018: 20 · 2017: 3
- FWCI
- 2.10
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Biophysical Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Health (NIH) National Institute of Neurological Disorders and Stroke (NINDS) (R01-NS047557)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Cerebrospinal fluid and hydrocephalus
- Keywords
- brain extracellular space, extracellular matrix, cerebrospinal fluid, Monte Carlo simulation, diffusion coefficient, macromolecular diffusion, intercellular spaces, chondroitin sulfate, heparan sulfate, bulk flow, glymphatic system
- MeSH terms
- Animals, Brain, Diffusion, Extracellular Space, Humans, Neurosciences, Molecular Imaging
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